Mammalian cells employ a collection of “DNA Damage
Responses”(DDRs) to protect and maintain genome stability.
These DDRs include cell-cycle checkpoints and DNA repair
mechanisms. As one can imagine, when these protective
mechanisms go awry, cells accumulate mutagenic damage, and
become vulnerable to genome instability and neoplastic
transformation.

My research aims to define the molecular regulations of
these DDRs. The ultimate goal is to translate this knowledge
to isolate better druggable targets and to develop more
accurate and sensitive biomarkers for genome
instability-associated syndromes. It is note-worthy to
mention that genetic inactivation of DDRs not only
contributes to cancer predisposition, but strikingly and
unfortunately, individuals that inherit DDR-targeting
mutations also manifest a variety of developmental deficits,
including those that compromise neuromotor skills. Because
of these reasons, I see an urgent need to understand how
cells respond to genotoxic stress, and perhaps more
specifically, how cells circumvent the deleterious effects
of DNA damage, which may otherwise jeopardise the survival
or quality of life of affected individuals. In addition,
because current cancer chemotherapeutic agents are often
themselves genotoxic compounds, it is important to
understand how cancerous cells may respond differentially to
these chemicals, such that maximal therapeutic potentials
can be achieved at the bedside.

One of my current research focuses centers on what is
commonly referred to as the DNA damage-signaling cascade.
This signaling cascade, activated by as little as one single
DNA double-strand break (DSB), is instrumental in
transducing DNA damage signals that culminate in the
coordinated execution of the collection of DDRs. In
particular, we have been very interested in studying how the
ubiquitin machineries modify damaged chromosomes to
sequester DNA damage mediator and repair proteins for
effective checkpoint control and DNA repair. We have studied
a number of positive regulators of this ubiquitin-dependent
DNA damage-signaling pathway, and have more recently begun
to look at how this pathway may be negatively regulated.
While it is easy to appreciate the need to sequester DNA
repair machineries at sites of DSBs, we recognise equal
importance in ensuring that DNA-modifying activities do not
excessively accumulate, especially at otherwise intact
chromosomal loci. How then do cells restrict DNA
damage-signaling to the vicinity of DSBs? We believe that
cells have evolved strategies to suppress unscheduled or
excessive accumulation of DNA damage mediator and repair
proteins, and we are currently investigating how the
functionalities of negative regulators of the DNA
damage-signaling pathway may be coupled to cell
proliferation and DNA repair.

Using breast and ovarian cancers as model systems, we have
also a keen interest in understanding how the BRCA1-BRCA2
protein network suppresses human tumorigenesis. Mutations of
BRCA proteins predispose individuals to early development of
breast and ovarian cancers. However, mechanistically how the
BRCA proteins suppress tumorigenesis has been a
long-standing question. Built upon our previous studies that
identified the Fanconi anemia protein PALB2 as the bridging
factor of the two BRCA tumor suppressors, we are currently
exploring the molecular regulation of the BRCA1-PALB2-BRCA2
axis in genome stability maintenance.

Sy SM, Huen MS, Chen J. PALB2 is an integral
component of the BRCA complex required for homologous
recombination repair. PNAS 2009;
106(17):7155-60. (Highlighted in Science –
“Complicated supercomplex”)
This paper identifies the Fanconi anemia protein PALB2 as
the bridging protein for the BRCA1 and BRCA2 tumor
suppressors. While the BRCA proteins share common roles in
suppressing human tumorigenesis, exactly how the two
proteins functionally interact has been a long-standing
question. By purifying PALB2-associated proteins, we found
that PALB2 interacted with both BRCA1 and BRCA2. We provided
evidence to show that the BRCA1-PALB2-BRCA2 complex promotes
homologous recombination and cell resistance to DNA damage.
Similar findings were independent reported by Yu Lab and
Andreassen Lab.